Characteristics of Autoimmune Hepatitis in Taiwan: the 11 Years Experiences of a Medical Center

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1 Chi nese Med i cal Jour nal (Taipei) 2002;65: Orig i nal Characteristics of Autoimmune Hepatitis in Taiwan: the 11 Years Experiences of a Medical Center Hui-Chun Huang 1 Yi-Shin Huang 1 Jaw-Ching Wu 1 Shyh-Haw Tsay 2 Teh-Ia Huo 1 Yuan-Jen Wang 1 Jing-Chuan Lo 1 Chih-Yen Chen 1 Chun-Ping Li 1 Full-Young Chang 1 Shou-Dong Lee 1 1 Di vi sion of Gastroenterology, De part ment of Med i cine, and 2 De part ment of Pa thol ogy, Tai pei Vet erans Gen eral Hos pi tal; and Na tional Yang-Ming Uni ver sity School of Med i cine, Tai pei, Tai wan, R.O.C. Key Words antinuclear an ti body; au to im mune hep a ti tis Background. Un like in West ern coun tries, au to im mune hep a ti tis (AIH) is an in fre quent di ag no sis in Tai wan. The clin i cal char ac ter is tics of AIH in this area are un clear. The aim of this study was to elu ci date the clin i cal fea - tures of AIH in Tai wan. Methods. All the med i cal re cords of in-patients with the di ag no sis of chronic hep a ti tis in our hos pi tal from 1990 to 2001 were re viewed for the pos si bil ity of AIH. The clin i cal fea tures, bio chem i cal data, im mu - no log i cal pre sen ta tions, treat ments and sur vival of the pa tients were eval u ated. Results. Twenty-two pa tients (15 fe males and 7 males) were di ag nosed as hav ing AIH within 11 years. The me dian age at on set was 64 years (range: years). Compared with fe male pa tients, male pa tients had older age (p = 0.001), shorter du ra tion from ini tial pre sen ta tion of symp toms to di - ag no sis ( p = 0.015), lower se rum lev els of al ka line phosphatase (ALK-P, p = 0.022) and al bu min (p = 0.043). Five (23%) pa tients pre sented with cir - rho sis upon di ag no sis. Compared with non-cirrhotic pa tients, cirrhotic pa - tients had lower serum lev els of alanine aminotransferase (p = 0.002), aspartate aminotransferase (p = 0.015), gamma-glutamyl transferase (G-GT, p = 0.002), al bu min (p = 0.14), white cell counts (p = 0.009) and platelet counts (p = 0.002). Thirteen (59%) patients had concomitant clinico-pathological fea tures of cholestatic liver dis ease (ALK-P 2 times of up per nor mal limit or patho logic ev i dence of cholangiopathy). They had higher se rum lev els of ALK-P (p < 0.001) and G-GT (p = 0.004) than 9 non-cholestatic pa tients. There were no sig nif i cant dif fer ences in sur - vival be tween these groups. The pre scribed ini tial and main tained prednisolone dos ages for our pa tients to con trol dis ease ac tiv ity were 19 ± 15 mg and 8 ± 1 mg, re spec tively, which were lower than those rec om - mended in West ern coun tries. The re mis sion rate to ste roid treat ment and re lapse rate af ter dis con tinu ing corticosteroids were 87.5% and 50%, re - spectively. Con clu sions. Compared with West ern AIH pa tients, the AIH pa tients in Tai wan are older and more likely to de velop cholestasis, and need a rel a - tively lower dose of ste roid for treat ment. Ow ing to one quar ter of the pa - tients already hav ing liver cir rho sis on di ag no sis, AIH should be sus - pected in any Tai wan ese pa tient with cryptogenic hep a ti tis or cir rho sis. [Chin Med J (Tai pei) 2002;65: ] Re ceived: March 4, Ac cepted: August 27, Cor re spon dence to: Yi-Shin Huang, MD, Di vi sion of Gastroenterology, De part ment of Med i cine, Tai pei Vet erans Gen eral Hos pi tal, 201, Sec. 2, Shih-Pai Road, Tai pei 112, Tai wan. Fax: ; yshuang@vghtpe.gov.tw

2 564 Hui-Chun Huang, et al. Chi nese Med i cal Jour nal (Taipei) Vol. 65 No. 12 Autoimmune hep a ti tis (AIH) is a chronic ac tive hep - a ti tis char ac ter ized by un re lent ing hepatocellular ne cro sis and the pres ence of spe cial se rum auto - antibodies. 1,2 This dis or der is not un com mon and has been well in ves ti gated in West ern coun tries. 3 Nev er - the less, the role of AIH in the pathogenesis of chronic hep a ti tis is likely to be ne glected in Tai wan that is an en demic area with hep a ti tis B and C vi ral in fec tion. To the best of our knowl edge, only spo radic cases of AIH have been re ported in Tai wan lit er a ture. 4 The clin i cal char ac ter is tics of AIH here are un known. The pur pose of this study was to in ves ti gate the clin i cal char ac ter is - tics of AIH in Tai wan. Sub jects Methods We ret ro spec tively re viewed all the med i cal re - cords of in pa tients with the di ag no sis of chronic hep a - ti tis (code of In ter na tional Clas si fi ca tion of Dis ease: ) upon dis charge from our hos pi tal from No - vem ber 1990 to Au gust Au to im mune hep a ti tis was di ag nosed based on the cri te ria pro posed by the In ter na tional Au to im mune Hep a ti tis Group. 5,6 It is a scor ing sys tem com posed of gen der, se rum liver bio - chem is try, serum glob u lin (or im mu no glob u lin G), antinuclear an ti body (ANA), anti-smooth mus cle an - ti body (ASMA), anti-mitochondrial an ti body (AMA), vi ral hep a ti tis mark ers, drug his tory, al co hol in take, liver histology, other au to im mune dis ease and re - sponse to ther apy. Def i nite AIH is di ag nosed when the ag gre gate scores are greater than 15 be fore treat - ment. 5,6 Prob a ble AIH is de fined if the scores are be - tween 10 and 15 be fore treat ment. 5,6 For strict di ag no - sis, we fur ther ex cluded the prob a ble cases who had (1) neg a tive se rum ANA; (2) pos i tive se rum AMA, hep a ti tis B sur face an ti gen, or hep a ti tis C an ti body; (3) im ag ing ev i dence of biliary tree ab nor mal i ties; (4) pos i tive causal re la tion ship of re cent drug in take and hepatic dys func tion; or (5) ha bit ual al co hol drink ing. The clin i cal char ac ter is tics in clud ing age, gen der, du - ra tion from the ini tial pre sen ta tion of symp tom to di - ag no sis, symp toms, signs, as so ci ated au to im mune dis ease, bio chem i cal data, serum ANA, ASMA, AMA and re sponse to treatment were re corded for fur ther eval u a tion. The se rum autoantibodies, in clud ing ANA, ASMA and AMA markers, were measured by an in di rect immunofluorescence as say using the Fluoro-Kit TM (Incstar Corp. Stillwater, Min ne sota, USA) ac cord ing to the man u fac turer s in struc tions. Liver bio chem i cal tests were measured by an auto-analyzer (Hitachi Model 736 au to matic an a lyzer; Hitachi, To kyo, Ja pan). Statistics Nu mer i cal data were ex pressed as mean ± SD. The Fisher s ex act test or Mann-Whitney U test was used to com pare the pa ram e ters be tween groups as appropriate. The Kaplan- Meier model with log rank test was per formed for sur vival anal y sis. A p value less than 0.05 was con sid ered sta tis ti cally sig nif i cant. Results Twenty-two (1.62%) of the 1,357 pa tients with chronic hep a ti tis were di ag nosed to have AIH, in - cluding 11 def i nite and 11 prob a ble cases ac cord ing to the Scoring sys tem. 5,6 The ini tial symp toms/signs are sum ma rized in Ta ble 1. Of the 22 AIH pa tients, 15 (68%) were fe males and 7 (32%) were males (Ta - ble 2). The me dian age upon the on set of symp toms was 64 years (range: years) whereas that upon Table 1. Initialsymptoms/signs of 22Chinese patients with autoimmune hepatitis Symptoms/signs No. (%) Poor appetite 5 (22.7) Abdominal fullness 5 (22.7) Fever 4 (18.2) Jaundice 4 (18.2) General malaise 3 (13.6) Nausea 2 (9.1) Abdominal pain 2 (9.1) Pruritus 2 (9.1) Fatigue 2 (9.1) Weight loss 2 (9.1)

3 De cem ber 2002 Au to im mune Hep a ti tis in Tai wan 565 Table 2. The characteristics of 22Chinese patients with autoimmune hepatitis before steroid treatment Parameters Patient values Reference values Age (years, upon onset) 54 ± 20 Age (years, upon diagnosis) 55 ± 20 Female/male 15/7 Duration (weeks) a 76 ± 184 ANA b 1:798 (1:80-1:2560) Undetectable ALT (U/L) 513 ± AST (U/L) 539 ± ALK-P (U/L) 218 ± G-GT (U/L) 275 ± DB (mg/dl) 4.1 ± TB (mg/dl) 5.6 ± Globulin (g/dl) 4.0 ± Albumin (g/dl) 3.5 ± IgG (mg/dl) 3,021 ± 1, ,560 WBC (/cumm) 5,454 ± 2,270 4,800-10,800 Hemoglobin (g/dl) 11.9 ± Platelet (/cumm) 175,368 ± 91, , ,000 Data are expressed as Mean ± SD except otherwise stated. a Duration: the time interval from initial symptoms to definite diagnosis; b geometric mean (range). ANA = antinuclear antibody; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALK-P = alkaline phosphatase; G-GT = gamma-glutamyl transferase; DB = direct bilirubin; TB = total bilirubin; IgG = immunoglobulin G; WBC = white blood cell count. Table 3. Comparison of pretreatment data between male and female patients with autoimmune hepatitis Parameters Male (n = 7) Female (n = 15) Age (years) a 72 ± 5 47 ± Duration (weeks) b 44 ± ± ALT (U/L) 603 ± ± AST (U/L) 555 ± ± ALK-P (U/L) 150 ± ± G-GT (U/L) 147 ± ± DB (mg/dl) 4.7 ± ± TB (mg/dl) 7.1 ± ± Globulin (g/dl) 4.1 ± ± Albumin (g/dl) 3.1 ± ± IgG (mg/dl) 3,400 ± 746 2,894 ± 1, WBC (/cumm) 5,791 ± 2,011 5,286 ± 2, Hemoglobin (g/dl) 12.7 ± ± Platelet (/cumm) 140,286 ± 62, ,833 ± 101, Data are expressed as Mean ± SD. a Age: upon diagnosis. b Duration: the time interval from initial symptoms to definite diagnosis. Abbreviated as Table 1. p diagnosis was 65 years (range: years). The pre - treat ment char ac ter is tics and re sults of lab o ra tory sur - vey of all AIH pa tients are shown in Table 2. Compared with fe male pa tients, the male pa tients dis - played older age, lower se rum al bu min and al ka line phosphatase (ALK-P) lev els upon the time of di ag no -

4 566 Hui-Chun Huang, et al. Chi nese Med i cal Jour nal (Taipei) Vol. 65 No. 12 Table 4. Comparison of pretreatment databetween cirrhotic and non-cirrhotic patients with autoimmune hepatitis Parameters Cirrhotic (n = 5) Non-cirrhotic (n = 17) Age (years) a 60 ± ± Female/male 3/2 12/5 Duration (weeks) b 209 ± ± ALT (U/L) 100 ± ± AST (U/L) 154 ± ± ALK-P (U/L) 177 ± ± G-GT (U/L) 71 ± ± DB (mg/dl) 0.9 ± ± TB (mg/dl) 1.7 ± ± Globulin (g/dl) 4.2 ± ± Albumin (g/dl) 2.8 ± ± IgG (mg/dl) 3,650 ± 1,143 2,875 ± 1, WBC (/cumm) 3,004 ± 1,465 6,048 ± 1, Hemoglobin (g/dl) 10.0 ± ± Platelet (/cumm) 79,600 ± 24, ,571 ± 81, Data are expressed as Mean ± SD. a Age: upon diagnosis. b Duration: the time interval from initial symptoms to definite diagnosis. Abbreviated as Table 1. Table 5. Comparison of pretreatment databetween cholestatic and non-cholestatic patients with autoimmune hepatitis Parameters Cholestatic (n = 13) Non-cholestatic (n = 9) Age (years) a 53 ± ± Female/male 10/3 5/4 Duration (weeks) b 44 ± ± ALT (U/L) 452 ± ± AST (U/L) 504 ± ± ALK-P (U/L) 269 ± ± G-GT (U/L) 381 ± ± DB (mg/dl) 3.2 ± ± TB (mg/dl) 3.4 ± ± Globulin (g/dl) 3.9 ± ± Albumin (g/dl) 3.7 ± ± IgG (mg/dl) 2,954 ± 1,399 3,106 ± WBC (/cumm) 5,308 ± 2,455 5,693 ± 2, Hemoglobin (g/dl) 10.0 ± ± Platelet (/cumm) 176,500 ± 70, ,111 ± 115, Data are expressed as Mean ± SD. a Age: upon diagnosis b Duration: the time interval from initial symptoms to definite diagnosis. Abbreviated as Table 1. p p sis (Ta ble 3). Five pa tients (23%) pre sented with cir - rho sis upon di ag no sis. They had sig nif i cantly lower se rum lev els of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (G-GT), al bu min, white blood cell count and platelet count (Ta ble 4). Thir teen (59%) pa tients

5 De cem ber 2002 Au to im mune Hep a ti tis in Tai wan 567 who had a more than 2-fold in crease of ALK-P and/or histologic ev i dence of biliary tree in jury were re - garded as cholestatic group (Table 5). They had higher se rum lev els of ALK-P and G-GT com pared with non-cholestatic pa tients (Ta ble 5). Four pa tients were as so ci ated with au to im mune dis eases, in clud ing 3 with Sjögren s syn drome and one with sys temic lupus erythematosus. Ste roid ther apy was in sti tuted to 16 pa tients. Two pa tients lost fol low-up af ter ini tial treat ment. The re - main ing 14 pa tients re sponded well (a de cline of ALT) in an av er age of 27 ± 13 days. The ALT level be - fore ste roid ther apy in sti tu tion was 697 ± 386 U/L and re sponded to the ther apy to fall to 71 ± 57 U/L. They ex pressed nor mal ized liver en zyme lev els (87.5%) af - ter an av er age of 57 ± 22 days. The av er age time of main te nance was 49 ± 40 months. The mean ini tial and main tained doses of prednisolone were 19 ± 15 mg and 8 ± 1 mg/day, re spec tively. Among the 14 pa - tients, 1 pa tient dis con tin ued ste roid treat ment due to per sis tent nor mal iza tion of liver bio chem is try tests; 4 pa tients un der went ta per ing of ste roids upon the end of our fol low-up; whereas 7 pa tients (50%) suf fered from ag gra va tion of liver bio chem is try data af ter ta - per ing ste roids. Ste roid ther apy was not pre scribed to 6 pa tients, be cause 5 of them were cirrhotic pa tients with nearly nor mal liver en zyme lev els and 1 pa tient lost fol low-up af ter clin i cal di ag no sis. Liver bi opsy was per formed in 12 pa tients, and had ev i dence of periportal necroinflammation (in ter - face hep a ti tis) (Fig. 1) in all. Con com i tant non spe cific biliary tree dam age was found in 9. Of these 9 pa - tients, 6 re sponded to ste roid ther apy well with nor - mal iza tion of liver en zyme lev els. The other 3 pa tients did not re ceive ste roid ther apy be cause of ini tial di ag - no sis of cir rho sis in 2 and loss of fol low-up in 1. Three pa tients died of liver cir rho sis with esoph a - geal variceal bleed ing, hepatic decompensation, and pneu mo nia with sep tic shock, re spec tively and 1 pa - tient lost fol low-up af ter di ag no sis, 2 pa tients lost fol - low-up af ter ini tial treat ment. There was no sig nif i - cant dif fer ence in sur vival be tween fe male and male pa tients (72 ± 12 vs. 54 ± 19 months, p = ), cholestatic and non-cholestatic (75 ± 9 vs. 55 ± 22 months, p = ), and cirrhotic and non-cirrhotic Fig.1. The liver pa thol ogy of an au to im mune hep a ti tis pa - tient re vealed mononuclear cell in fil tra tion at the peri-portal zone, with ne cro sis or de gen er a tion of hepatocytes, which shows a typ i cal char ac ter is tic of interphase hep a ti tis (H&E stain, 40 X). pa tients (81 ± 43 vs. 65 ± 9 months, p = ). Discussion AIH is a dis ease of un known eti ol ogy, char ac ter ized by female predominance, hypergammaglobulinemia, cir cu lat ing an ti bod ies, hepatocytic dam age, and marked re sponse to immunosuppressive ther apy. 1,2 Ac cu rate di ag no sis for AIH is in deed im por tant for an ap pro pri ate ther apy. 7 How ever, the spec trum of au to - im mune hepatic in jury var ies mark edly from pure hepatocytic to biliary ep i the lial dam age, 1,8,9 which oc - ca sion ally makes the dis tinc tion quite dif fi cult. Since the cur rent study was per formed ret ro spec tively, to avoid cases with con tro ver sies re gard ing in ad e quate study or in def i nite di ag no sis, out-patients and those with AMA positivity were ex cluded. Se lec tion bias may be pres ent un der such a set ting, but the re main ing cases can be eval u ated as an AIH group un doubt edly. Au to im mune hep a ti tis can be clas si fied as type 1 with the pres ence of ANA, ASMA and type 2 with liver-kidney microsomal an ti body (LKM1). 10,11 Fur - ther more, the re la tion ships of AIH clas si fi ca tion and clin i cal char ac ter is tics to HLA-DR3 and -4 status have been re ported. 12 Due to the ret ro spec tive na ture of our study, how ever, LKM1 and HLA tests were not

6 568 Hui-Chun Huang, et al. Chi nese Med i cal Jour nal (Taipei) Vol. 65 No. 12 per formed upon ini tial pre sen ta tion of the pa tients. In our se ries, fe male to male ra tio was 2.1, which was sig nif i cantly lower than that re ported for the Jap a - nese (ra tio: 6:1) 13 and for the West erns (ra tio: 8:1). 14 It may count that our hos pi tal serves mainly for vet er ans. Al though AIH usu ally af fects young fe males and the meno pause women in West ern ar eas, 3,14 our AIH pa - tients seemed older at on set (54 ± 20 years). Sim i larly, two Jap a nese se ries re ported the on set at older age, too (50 and 70 years, re spec tively). 13,15 Thir teen of our AIH pa tients had el e vated ALK-P and G-GT lev els and/or cholangiopathy ver i fied by pa thol ogy. How ever, the fol low ing rea sons still sup - port the di ag no sis of AIH in these pa tients: 1) high ti - ter of ANA with out AMA; 2) el e vated se rum lev els of im mu no glob u lin G in stead of M, which is con sis tent with the fea tures of AIH rather than pri mary biliary cir rho sis (PBC); 3) the ab sence of biliary tree dis ease to de velop over a me dian fol low-up of 91 months; 4) ex cept 2 pa tient lack ing fol low-up, those who re - ceived corticosteroid ther apy sig nif i cantly im proved with nor mal iza tion of liver bio chem is try data. This fur ther sup ported the di ag no sis of AIH; 16 and 5) no biliary tree ab nor mal ity iden ti fied by sonography. The cause of a higher per cent age of cholestatic pa tients in our AIH pa tients, how ever, re mains to be clar i fied. Au to im mune cholangitis can be very sim i lar to PBC re gard ing its clin i cal, bio chem i cal, and histo - pathological fea tures ex cept neg a tive AMA and pos i - tive ANA. Its clas si fi ca tion in the field of au to im mune liver dis ease re mains un cer tain. 17,18 Autoimmune cholangitis may be a vari ant of pri mary biliary cir rho - sis. 18,19 Though un cer tainty ex ists, all of our pa - tients, ex cept 5 cirrhotic pa tients, had at least 3-fold el e va tion of alanine transaminase lev els and/or patho - log i cal ev i dence of interphase hep a ti tis. Con se - quently, the di ag no sis of AIH with cholestatic fea tures rather than au to im mune cholangitis was es tab lished. In the West ern ex pe ri ences, the rec om mended ini - tial dose of prednisolone is 60 mg/day, and the main te - nance dose is 20 mg/day. 2 In con trast, we pre scribed the lower doses for the AIH pa tients (the ini tial and main te nance doses of prednisolone were 19 ± 15 and 8 ± 1 mg, re spec tively). The re mis sion rate in our se - ries was 87.5%, which was com pa ra ble with that of a Sin ga pore se ries (89%) 23 but higher than the West ern re ports (65%). 24 The av er age time to re mis sion was also sig nif i cantly shorter in our group than in the Westerns. 24 Whether the Asian AIH pa tients ex ert the higher treat ment re spon sive ness and the lower dose re quire ment to ste roid re main to be clar i fied. Five (23%) pa tients were found to de velop cir rho - sis upon di ag no sis. This im pli cates that the pa tient may de lay to con sult med i cal aids or the lo cal phy si cians may over look to di ag nose AIH. The mean sur vival of cirrhotics was not sig nif i cantly dif fer ent from that of non-cirrhotics, which may be re lated to the rel a tively small num ber of cirrhotic pa tients in our se ries. Ac cord ing to the cur rent sur vey, non-cholestatic pa tients pre sented with higher lev els of to tal and di rect bil i ru bin than cholestatic pa tients, though sta tis ti cal sig nif i cance was not found. The pos si ble ex pla na tion is that the non-cholestatic pa tients are more likely to have hepatocellular dam age, in stead of biliary tract in jury, than cholestatic pa tients. Pro found hepatocellular dam - age may cause jaun dice. The fol low ing con di tions may sup port this in fer ence. First, com pared with cholestatic cases, non-cholestatic cases tended to have higher lev - els of ALT and AST, al though the dif fer ence was not sta tis ti cally sig nif i cant. This may im pli cate the more ac tive pro cess of hepatocellular de struc tion and ne - cro sis in non-cholestatic cases. As cases that re ceived liver pa thol ogy sur vey in this group were lim ited, this point of view can still not be patho log i cally con firmed at pres ent. Sec ond, 4 out of 5 cirrhotic pa tients were non-cholestatic. Among them, 1 pa tient evolved into liver decompensation with re mark ably high lev els of to tal and di rect bil i ru bin. This may cause high mean bil i ru bin level in non-cholestatic group. In sum mary, cholangiopathy and cir rho sis are not un com mon in our Chi nese AIH pa tients, and they tend to be older than West ern pa tients. Since it can be con - trolled with a lower dose of ste roid here, the di ag no sis of AIH should be kept in mind when ever a Chi nese pa tient with cryptogenic hep a ti tis is un der eval u a tion. References 1. John son PJ, McFarlane IG, Eddleston ALWF. The nat u ral

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